**Core Concept**
Sickle cell anemia is a genetic disorder caused by a mutation in the HBB gene, which codes for the beta-globin subunit of hemoglobin. This mutation leads to the production of abnormal hemoglobin, known as hemoglobin S (HbS), which causes red blood cells to become misshapen and rigid, leading to their premature destruction.

**Why the Correct Answer is Right**
The mutation leading to sickle cell anemia is a point mutation in the HBB gene, resulting in the substitution of glutamic acid (Glu) with valine (Val) at position 6 of the beta-globin chain. This substitution causes hemoglobin S to polymerize under low oxygen conditions, leading to the characteristic sickle shape of red blood cells. The polymerization of hemoglobin S disrupts the normal flexibility of red blood cells, causing them to become rigid and prone to premature destruction.

**Why Each Wrong Option is Incorrect**
**Option A:** This option is incorrect because the mutation leading to sickle cell anemia is not caused by a frameshift mutation, but rather a point mutation that results in a specific amino acid substitution.

**Option B:** This option is incorrect because the mutation leading to sickle cell anemia is not caused by a deletion of the HBB gene, but rather a specific point mutation within the gene.

**Option C:** This option is incorrect because the mutation leading to sickle cell anemia is not caused by a duplication of the HBB gene, but rather a specific point mutation within the gene.

**Clinical Pearl / High-Yield Fact**
Sickle cell anemia is a classic example of a genetic disorder caused by a single point mutation, highlighting the importance of precise genetic testing and counseling for individuals and families affected by this condition.

**Correct Answer: D. Glutamic acid (Glu) substitution with valine (Val) at position 6 of the beta-globin chain.**